1) Host Pathogenesis Given the relatively lower virulence of many of the nontuberculous mycobacteria (NTM), the sometimes indolent onset of symptoms, and the difficulty of treatment relative to tuberculosis, many elect not to treat or to have their infections treated. However, it is clear that these chronic infections in the setting of bronchiectasis can lead to advanced lung disease and death in some patients. Recent work focused on the cohort of patients followed at the NIH Clinical Center with idiopathic bronchiectasis and chronic NTM lung infections sought to assess the occurrence and predictors of mortality in this population. This study was a follow-on to previous published work describing the histopathologic and radiographic characteristics of this disease in an autopsy series from the NIH cohort. A cohort of 106 well characterized patients with bronchiectasis and chronic NTM lung infection followed at the NIH for a median of 4.9 years was assessed in a retrospective study. During the follow-up period, 27 (29%) died yielding a mortality of 4.2 per 100 person-years. As with other reports in this disease, the cohort was predominantly female (88%) and white (88%). Fibrocavitary disease (aHR 3.3, 95%CI 1.3-8.3) and pulmonary hypertension (aHR 2.1, 95%HR 0.9-5.1) were significant predictors of mortality. Significant collaborative work continued to establish research priorities for NTM lung disease and guidelines for effective diagnosis and management of NTM in the setting of cystic fibrosis. Rapid advances in the genetics of primary ciliary dyskinesia (PCD - a known cause of bronchiectasis) and improvements in defining clinical and an effective surrogate pathophysiology-based screening test (real time nasal nitric oxide production) coming from the NHLBI/NCATS sponsored Genetic Diseases of Mucociliary Clearance Consortium led to creation of consensus recommendations for diagnosis, monitoring, and management of PCD. Formal guidelines are nearing completion through the American Thoracic Society. 2) Environmental exposure and epidemiology of bronchiectasis and nontuberculous mycobacterial lung disease Continued collaborative work utilizing the Cystic Fibrosis Patient Registry database demonstrated the evolving epidemiology of lower airway infections in the CF population. From 2006 to 2012 there was a general decrease in prevalence of the deleterious pathogens Pseudomonas aeruginosa and Burkholderia cepacia and prevalence of methicillin resistant Staph aureus increased. From 2010 (first year NTM were tracked with sufficient detail) to 2012, an increase in prevalence of NTM and in particular Mycobacterium avium complex was noted. These changes likely reflect changes in the management and increased life span of CF patients. NTM are of increasing concern in CF as a cause of morbidity and mortality. 3) Microbial pathogenesis Mycobacterium abscessus has been associated with significant lung disease and increased morbidity and mortality especially in the setting of CF. Resistance to macrolides can either be through an acquired mutational change or an inheritant induction via the erm 41 gene, the function of which can vary between subspecies of M. abscessus. Detection of these resistance mechanism can be either through lengthy co-culture of the organism with a macrolide or via a newly developed rapid PCR assay. Work in the lab over the past year has focused on development of an amoeba model to assess relative virulence of fully genotyped M. abscessus isolates with a goal of identifying relevant virulence targets for potential therapeutic intervention. 4) Drug development The treatment of PNTM disease requires prolonged, multi-drug, poorly tolerated regimens of limited efficacy. Prior work has shown efficacy and improved toxicity of amikacin delivered via inhalation to patients with treatment refractory NTM infections. Work over the past year has focused on completion of data analysis and manuscript submission for reporting results of the first multi-site clinical trial of a novel agent, liposomal encapsulated amikacin for inhalation, for management of treatment refractory M. avium complex and M. abscessus lung disease. Publication of the results of this trial completed with CRADA partner Insmed, Inc. are pending at the time of this report. The completion and success of this trial has led to increased focus on drug development and trial design for NTM disease by the FDA and increased interest among biotech and pharmaceutical companies for directing relevant drugs in development toward this indication.